Haematology + Oncology News (Vol.9_No.2)

Vol. 9 • No. 2 • 2016

The Leading Independent Newspaper from Elsevier

Immune checkpoint inhibitors have antitumour activity in gastric, oesophageal cancers

right direction,” Dr Möhler said, recommending that it be correlated with data from The Cancer Genome Atlas project, which has identified four distinct molecular subtypes of oesophagogastric cancer. “It is now clear that some of these subtypes express higher PD-L1 compared to the others, particularly inflamed subtypes,” he elabo- rated. “Therefore, it is clear that all the studies in the future really should try to look into the correlation with these four gene subgroups characterised.” CHECKMATE-032 TRIAL Patients with a variety of solid tumours were eligible for CheckMate-032, a phase I/ II trial. First author Dr Dung T. Le reported results for 59 patients with locoregionally advanced or metastatic gastric cancer, oesophageal, or gastro- oesophageal junction cancer who had received at least one prior therapy. The patients were treated with nivolumab every 2 weeks. (Nivolumab is currently TGA approved for the treatment of melanoma, non-small cell lung cancer, and in combination with ipilimumab for metastatic (stage IV) melanoma.) With a median follow-up of 4.6 months, the response in complete enzyme recovery at 24 hours. Nanoparticles inhibited tumour growth by over 90%, compared with 58% for the free drug at twice the dose, and showed little toxicity as evidenced by stable body weight. Na- noparticles were retained in the tumour xenografts for up to 6 days, while the free drug was undetected in tumours 24 hours after administration. “Although we selected a lead formulation using a tumour model (SW620) that supported the AZD1152 program – and, as such, we had extensive comparator data from which to benchmark the tolerability, PD, and efficacy of candidate nanoparticles – the model is subject to the known limita- tions of xenografted human tumour cell lines in assessing therapeutic candidates in oncology. Moreover, although rat bone marrow is commonly rate was 14%, reported Dr Le of Sid- ney Kimmel Comprehensive Cancer Center, Johns Hopkins, Baltimore, at the symposium, which was sponsored by ASCO, ASTRO, the American Continued on page 2.

IN THIS ISSUE

Acupressure improves persistent fatigue in breast cancer survivors 3 Minimal residual disease a powerful prognostic factor in AML 5

BY SUSAN LONDON Frontline Medical News At the Gastrointestinal Cancers Symposium, San Francisco T wo immune checkpoint inhibitors that help restore the antitumour response are active and well tolerated in patients with advanced, generally heavily pretreated gastric and oesophageal cancers, according to a pair of early-phase trials reported at the Gastrointestinal Cancers Symposium. Results from CheckMate-032 showed that nivolumab, an antibody that targets the cell surface recep- tor programmed death-1 (PD-1), yielded a response rate of 14% in patients with advanced gastric and related cancers. And updated results from KEYNOTE-028 showed that pembrolizumab, another antibody targeting PD-1, led to a response rate of 30% in patients with advanced oesophageal and related cancers that expressed the ligand programmed death ligand 1 (PD-L1). “Checkpoint inhibitors are clearly promising new agents ... All com- pounds are still in development, but we already have at least phase 1 data that they are effective,” commented invited discussant Dr Markus H. Möhler of the University Medical Center Mainz (Germany). “Combina- tion treatment strategies are clearly

Intense tumour lymphocytic infiltration indicates favourable prognosis in NSCLC 7

ASCO Gastrointestinal Cancers Symposium

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More GCS stories inside!

Everolimus is effective across diverse patients with GI neuroendocrine tumours Wide disparity in radiology reads without RECIST Bipolar androgen therapy may be new option for hormone-sensitive prostate  cancer 11 Immune-related events with checkpoint inhibitors are manageable 14 Prostate cancer – year in review 15

development of a tumour gene signa- ture that appeared to predict benefit from pembrolizumab. “Molecular and immunological characterisation of the patients is key, and we have seen now in the pembrolizumab study with the six- gene signature the first step in the

under investigation, and it is our task as a scientific community to look into interesting modern combinations, like combinations with antiangiogenic agents or maybe even with stem cell inhibition.” He commended theKEYNOTE-028 investigators, in particular, for their

Nanoparticles deliver Aurora kinase inhibitor with increased safety and efficacy

are composed of block co- polymers of poly-D,L-lactide (PLA) and poly(ethylene glycol) (PEG). Accurins accu- mulate in tumours, increas- ing the drug’s concentration and duration of exposure to the cancer cells. Organic acid counterions were used to increase encapsulation efficiency and decrease the release rate of AZD2811. “We identified a formula- tion profile that could deliver active drug for more than 1  week, resulting in pro- longed target inhibition in tumour tissue together with improved preclinical efficacy and therapeutic index over the AZD1152 prodrug in several animal models,” they wrote. In nude rats bearing human colorectal adenocarcinoma SW620 xenografts, the na- noparticles inhibited kinase over a 96-hour time course, while the free drug resulted

in a phase II trial. Efficacy, however, was associated with major toxicities, including myelosuppression. Further, AZD1152 had to be admin- istered as a 7-day continuous intravenous infusion. By using the Accurin nano- particle platform to vary drug release kinetics, the research- ers devised a formulation to maximise the therapeutic effect of the kinase inhibitor while sparing healthy tissue. AZD1152 is a water-soluble prodrug of AZD2811, which the researchers used to de- velop their the nanoparticle formulation. AZD2811 was encapsu- lated in polymeric nanoparti- cles termed Accurins, which

range of haematological and solid tumour cancer indica- tions,” wrote Susan Ashton of AstraZeneca, and her colleagues. “The improved bone mar- row profile observed with slow-releasing nanoparticles may enable efficacious com- bination treatments” with chemotherapy, radiotherapy, or poly(adenosine diphos- phate-ribose) polymerase (PARP) inhibitors. The study was under- taken because a free-drug version of the agent, known as AZD1152, had led to a significant improvement in the complete response rate of acute myeloid leukaemia compared to standard of care

BY JENNIFER SHEPPHIRD Frontline Medical News From Science Translational Medicine U sing nanoparticles to encapsulate an Aurora B kinase inhibitor improved the efficacy and tolerability of the drug and allowed less frequent dosing in preclini- cal models, according to re- searchers ( Sci Transl Med 2016 Feb 10. doi: 10.1126/ scitranslmed.aad2355). “The AZD2811 nanoparti- cles identified in this study have the potential to increase efficacy at tolerable doses us- ing a more convenient dosing regimen, which may in turn extend the utility of Aurora B kinase inhibition to a broader

used to model myelotoxicity in humans, interrogation of the nanoparticle dose and sched- ule in patients may be required to achieve optimal clinical re- sults,” they concluded. AstraZeneca funded the study. Dr Ashton and several coau- thors are current or former employees and shareholders of AstraZeneca or BIND. The companies are developing the drug and technologies.

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